PROJECT SUMMARY Tumor plasticity and the development of multidrug resistance (MDR) remain the most important challenge in clinical cancer therapy, especially in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). We hypothesize that phenotypic and epigenetic genetic reprogramming of tumor cells in NSCLC and OC would significantly improve the therapeutic response, especially in refractory disease. The main objective of the NCI's Innovative Research in Cancer Nanotechnology (IRCN) (PAR-14-285) application is to develop and evaluate an innovative microRNA (miR)-based phenotypic and epigenetic cellular reprogramming approach using a highly versatile dual-targeted hyaluronic acid (HA)-based nanoplatform to eradicate acquired MDR. This objective is consistent with the IRCN guideline for possible research direction in developing ?techniques and tools to overcome failure of therapy?. Our preliminary results show that dual EGFR/CD44-targeted HA nanoparticles loaded with miR-34a expressing mimics were effective in transgene expression, altered nuclear and mitochondrial epigenetic markers in A549 wild-type and A549DDP cisplatin-resistant NSCLC models in vitro and in vivo. The specific aims of the application are as follows: (1) ?Click? synthesis of HA-based functional blocks and efficient encapsulation of miR-34a and Let7a mimics by aqueous self-assembly for dual EGFR/CD44- targeted delivery; (2) evaluate transfection, phenotypic, and epigenetic reprogramming with miR-34a and Let7a mimics in wild-type and drug resistant A549 NSCLC and SKOV3 OC cells and 3D spheroids models; (3) examine in vivo tumor targeting, biodistribution, and quantitative pharmacokinetic profiles with control and dual EGFR/CD44-targeted HA-based nanoparticles in orthotopic wild-type and resistant A549 NSCLC and SKOV3 OC tumor models; (4) evaluate in vivo transfection and cellular reprogramming with systemically-administered miR-34a and miR-Let7a mimics in orthotopic wild-type and resistant NSCLC and OC tumor models; and (5) examine the therapeutic efficacy and acute safety profiles of miR transfection with chemotherapy in orthotopic wild-type and resistant NSCLC and OC tumor models. This study is clinically significant as a strategy for enhancing the therapeutic efficacy of MDR cancer treatment through cellular reprogramming by using a miR-based therapeutic approach to phenotypically and epigenetically reprogram NSCLC and OC. Our HA-based nanoparticle platform is highly innovative and versatile for dual EGFR/CD44 targeted and intracellular delivery of nucleic acid constructs in orthotopic refractory NSCLC and OC tumors.